Studies on the mechanisms underlying renal tubular deficiency due to the lack of the expression and function of CLCN5, a gene responsible for Dent's disease

CLCN5（一种导致 Dent 病的基因）表达和功能缺失导致肾小管缺陷的机制研究

• 批准号: 13672287
• 负责人: TAKANO Mikihisa
• 金额: $ 2.3万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672287/
• 关键词: Dent's disease; chloride channel; ClC-5; endocytosis; proteinuria; hypercalciuria; receptor; renal tubules; 高カルシウム尿症; 培養腎上皮細胞; エンドソーム内酸性化; 蛋白尿; 遺伝性腎疾患

Dent's disease is a X-linked recessive nephrolithiasis associated with various renal dysfunctions such as proteinuria and hypercalciuria. Recently, CLCN5, a gene encoding chloride channel ClC-5, was found to be responsible for Dent's disease, though the precise role of ClC-5 is not known at this moment. ClC-5 is highly expressed in the kidney, where the channel is involved in the acidification of endosomes, an important step for receptor-mediated endocytosis. On the other hand, proteins filtered through glomerulus are efficiently taken up by tubular cells by receptor-mediated endocytosis. In the present study, I examined the role of ClC-5 in renal handling of proteins and calcium.Cultured renal epithelial cells OK were used as a model system, which I confirmed the expression of ClC-5. When cells were treated with chloride channel inhibitors, the endocytosis of FITC-labeled albumin was inhibited. In addition, the uptake of calcium by OK cells was inhibited by chloride channel inhibitors as well as by anti-ClC-5 antibody. Therefore, C1C-5 would have an important role for the endocytosis of filtered protein and calcium uptake in the kidney. These results may explain the proteinuria and hypercalciuria observed in Dent's disease, in which ClC-5 is lacking.

登特氏病是一种X连锁隐性肾结石，伴有各种肾功能障碍，如蛋白尿和高钙尿。最近，发现编码氯离子通道ClC-5的基因CLCN 5与登特氏病有关，尽管目前尚不清楚ClC-5的确切作用。ClC-5在肾脏中高度表达，其中通道参与内体的酸化，这是受体介导的内吞作用的重要步骤。另一方面，通过肾小球过滤的蛋白质通过受体介导的内吞作用被肾小管细胞有效地摄取。在本研究中，我检查了ClC-5在肾脏处理蛋白质和钙的作用。培养的肾上皮细胞OK被用作模型系统，我证实了ClC-5的表达。当细胞用氯离子通道抑制剂处理时，FITC标记的白蛋白的内吞被抑制。此外，通过OK细胞的钙的摄取被抑制的氯离子通道抑制剂，以及通过抗-ClC-5抗体。因此，C1 C-5对肾脏中过滤蛋白的内吞作用和钙摄取具有重要作用。这些结果可以解释在Dent病中观察到的蛋白尿和高钙尿，其中ClC-5缺乏。

项目成果

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Sasaki, Y. et al.: "Expression of chloride channel, ClC-5, and its role in receptor-mediated endocytosis of albumin in OK cells"Biochem. Biophys. Res. Commun.. 282. 212-218 (2001)

Sasaki, Y. 等人：“氯离子通道 ClC-5 的表达及其在 OK 细胞中受体介导的白蛋白内吞作用中的作用”Biochem。

Sasaki, Y. et al.: "Expression of chloride channel, ClC-5, and its role in receptor-mediated endocytosis of albumin in OK cells"Biochem. Biophys. Res. Commun. 282・1. 212-218 (2001)

Sasaki，Y.等人：“氯通道ClC-5的表达及其在OK细胞中受体介导的白蛋白内吞作用”Biochem.Biophys.282·1。

Takano, M. et al.: "Cisplatin-induced inhibition of receptor-mediated endocytosis of protein in the kidney"Kidney Int.. 62. 1707-1717 (2002)

Takano, M. 等人：“顺铂诱导的肾脏中受体介导的蛋白质内吞作用的抑制”Kidney Int.. 62. 1707-1717 (2002)

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Nagai，J.等：“巨蛋白在氨基糖苷类肾处理中的作用”Am.J.Physiol..281.F334-F344(2001)